Tolerance of myocardium of aged animals to repeated oxygen deficiency

Summary Hemodynamic and metabolic effects of three times 4 min of oxygen deficiency were investigated in 18-month-old rats in comparison to 4-month-old Wistar rats. Left-ventricular isovolumicpressure-generating capacity and dp/dt_max during isovolumic conditions and hemodynamic indices during intact circulation were determined in open-chest rats. Additionally, high-energy phosphates were measured at the end of the experiments after 20 min of postasphyxial recovery.Older rats had a significantly reduced isovolumic left-ventricular pressure generating capacity (236±9 vs 269±5 mm Hg; p<0.05) and a low cardiac index (55±9 vs 117±8 ml×min^–1×kg^–1). The effects of the oxygen deficiency were comparable in both groups. The isovolumic pressure generating capacity was reduced for 11% vs 14%, and dp/dt_max for 13% vs 13%. The myocardial ATP-content was also decreased for the same extent in both groups (0.6 vs 1.0 mol/gww). Both hemodynamic and biochemical results indicate that aged myocardium does not have a reduced tolerance to repeated periods of oxygen deficiency.Supported in part by the Deutsche Forschungsgemeinschaft, Bonn, FRG (HO 1003/1-2)Parts of the results were presented at the 10th meeting of the Internat. Soc. for Heart Research (Europ. Section), Rotterdam, 1989     

Alanine,glutamate, and ammonia exchanges in acutely ischemic swine myocardium

Summary Coronary artery disease causes an increase in glutamate uptake and alanine output by the heart. We assessed the effects of acute myocardial ischemia on alanine and glutamate exchange and ammonia production in 10 anesthetized open-chest domestic swine (46.9±0.7 kg). Coronary blood flow was controlled through an extracorporal perfusion circuit. After a nonischemic control period (aerobic) the blood flow in the left anterior descending coronary artery was reduced by 60%. Arterial and anterior interventricular venous samples where drawn before and during 35 min of ischemia. Subendocardial blood flow, measured using radiolabeled microspheres, decreased from 1.27±0.16 to 0.25±0.09 (ml/g)/min, and left-ventricular wall-thickening fell to 47% of aerobic values. Ischemia resulted in a significant increase in the rate of glucose uptake (p<0.05) and a switch to net lactate production (p<0.01). Ischemia did not affect the rates of alanine output (–0.9±1.0 vs. –0.3±0.3 mol/min) or glutamate uptake (–0.4±1.1 vs. 0.3±0.6 mol/min), but did increase the venous-arterial difference for ammonia (–4.1±4.1 to 52.7±5.5 M, p<0.0001) and the ammonia output (–0.33±0.24 to 1.34±0.14 mol/min, p<0.0001). In conclusion, acute ischemia did not stimulate greater alanine output or glutamate uptake. However, acute ischemia did cause an increase in anaerobic glycolysis rate and ammonia output, which reflects a profound disruption in myocardial energy metabolism.     

Stereoselective electrophysiological effects of propafenone in Langendorff perfused guinea pig hearts

Summary The present study was focused on the stereoselective electrophysiological effects of (R)-and (S)-propafenone·HCl evaluated in isolated Langendorff perfused guinea pig hearts. Conduction intervals were measured using an ECG-recording method of high resolution. Refractory periods of the different parts of the myocardium were determined by stimulation with premature stimuli, as well as by stimulation with increasing pacing rate (rate-dependent/refractory periods). Drug concentrations of 0.1, 1 and 3 M were tested. Both compounds induced a dose-dependent increase in AV-nodal, His-bundle, and intraventricular conduction time which reached significance (p<0.01) following 3 M of either compound. Sinus rate was also dose-dependently and significantly reduced.(R)- and (S)-propafenone·HCl induced a marked prolongation of the rate-dependent refractory period of sino-atrial (by 140±22%, p<0.01 and by 141±14%, p<0.01, respectively) and AV-nodal (by 34±22%, p<0.01 and by 42±15%, p<0.01, respectively) conduction and of the atrial (by 182±21%, p<0.01 and by 195±15%, p<0.01, respectively) and ventricular (by 93±16%, p<0.01 and by 88±16%, p<0.01, respectively) myocardium. The effective refractory periods evaluated by stimulation with premature stimuli were also significantly prolonged under the influence of (R)- and (S)-propafenone·HCl, except the ventricular myocardial refractoriness by (R)-propafenone·HCl (increase to 114±23%, n.s.). Both compounds showed a strong rate-dependence of their effects and, thus, the refractory periods evaluated by stimulation with increasing pacing rate were significantly more prolonged than the refractory periods evaluated by stimulation with premature stimuli. The main difference between the effects of (R)- and (S)-propafenone·HCl on the cardiac electrical activity is the lack of effect of (R)-propafenone·HCl on the ventricular myocardial refratoriness evaluated by stimulation with premature stimuli.Supported by the Austrian Research Foundation grant P7141, P8014, P8184     

Reduced neuronal noradrenaline overflow in the ischaemic rat heart: Importance of the severity of coronary flow reduction

Summary The effects of severity and duration of acute myocardial ischaemia on left stellate ganglion stimulation-induced noradrenaline (NA) overflow were studied in the retrogradely perfused, innervated rat heart. A 10-min period of ischaemia induced by a coronary flow reduction of 100% (0 ml/g/min), 95% (0.24 ml/g/min) and 90 % (0.48 ml/g/min) reduced neuronal NA overflow to 24 ± 4% (p < 0.01), 62 ± 6% (p < 0.05) and 70 ± 6% (p < 0.05) of the normoxic control values, respectively. During low-flow ischaemia, a progressive decline in neuronal NA overflow was found in hearts subjected to 95 flow reduction, but not to 90% flow reduction.The effect of ischaemia on presynaptic control of NA release was also examined. After 10 min of stop-flow ischaemia, the -adrenergic antagonist phentolamine (1 M) and the adenosine receptor antago-nist 8-phenyltheophylline (10 M) failed to restore neuronal NA overflow to pre-ischaemic levels (from 24 ± 4% without drug to 23 ± 4% or 41 ± 10%, respectively, NS). In contrast, after 60 min of low-flow ischaemia (95% flow reduction), phentolamine and 8-phenyltheophylline largely restored neuronal NA overflow to normoxic control values (from 32 ± 3% without drug to 61 ± 11% (p < 0.05) or 79 ± 11 (p < 0.01), respectively).During prolonged low-flow ischaemia (95%), the neuronal NA reuptake inhibitor desipramine (0.1 M) doubled NA overflow induced by nerve stimulation, suggesting an effective neuronal reuptake during these conditions.In conclusion, the severity of ischaemia critically affects neuronal NA release and its controlling mechanisms. Thus, heterogeneity of myocardial ischaemia may lead to gradients in NA release and myocardial adrenergic stimulation.     

Alterations in the myocardial capillary vasculature accompany tachycardia-induced cardiomyopathy

Summary Changes in capillary structure and distribution within the left ventricle (LV) occur with pressure and volume overload hypertrophy. These changes may cause an impairment in myocardial blood flow (MBF) and oxygen delivery resulting in myocyte injury and LV dysfunction. However, it is unknown whether changes in the capillary vasculature accompany the development of LV dysfunction in dilated cardiomyopathies. Accordingly, this study examined the relation between LV function, MBF and capillary architecture after the development of dilated cardiomyopathy in pigs produced by chronic supraventricular tachycardia (SVT). LV function was examined by echo-catheterization, and capillary morphometrics were computed using lectin histochemistry in two groups of pigs: sham controls (n=8); and after 3 weeks of pacing-induced SVT (n=8). Chronic SVT resulted in significantly incresed LV end-diastolic dimension and pressure with a 50% reduction in LV fractional shortening compared to CON (p<0.05). Although no significant change in capillary density (2180±164 vs 2402±147/mm², p=0.25) occurred in the SVT group compared to CON, a significant reduction in the volume fraction of capillaries (12.2±0.5 vs 9.9±0.7%, p<0.05) and increased capillary diffusion distance (8.4±0.5 vs 7.5±0.3 m, p<0.05) was observed. Frequency distribution analysis revealed a higher percentage of smaller diameter capillaries with chronic SVT vs CON (p<0.05). Ultrastructural examination revealed an increased capillary-myocyte distance with chronic SVT (0.95±0.08 vs 1.95±0.12 m, p<0.05). These changes were accompanied by ultrastructural evidence of significant subendocardial injury (p<0.05). MBF was measured using microspheres in five additional conscious pigs in each group. MBF was significantly reduced and coronary vascular resistance increased in the SVT group compared to CON (p<0.05). Chronic SVT caused significant remodeling of the capillary vasculature; these changes were associated with reduced MBF, myocyte injury, and LV dysfunction.     

Adenosine-induced increase in myocardinal ATP: Are there beneficial effects for the ischaemic myocardium?

Summary The adenosine triphosphate (ATP) content of isolated Langendorff-perfused rat hearts may be increased by more than 40% above the normal value by a 2-h perfusion with adenosine (15 mol/l). This metabolic manipulation was used to investigate the hypothetical relationship between total tissue ATP content and ischaemia-induced contractile failure, ischaemic contracture and post-ischaemic functional recovery.Adenosine perfused hearts were submitted to 20 min of normothermic ischaemia and reperfused for 45 min with or without adenosine. Control experiments were performed with adenosine-free preischaemic perfusion. In identically designed experiments the tissue-protective effect of diltiazem (0.5 mol/l) was determined and compared with the experiments with adenosine.At the end of 120 min of preischaemic perfusion, the ATP content of the adenosine treated hearts was 34.3±1.8 mol/g dry weight (control=23.6±1.9 mol/g, p<0.01). After a period of 20 min of normothermic ischaemia, the ATP content of the adenosine hearts decreased to 13.3± .4 mol/g, whereas ATP fell to 8.3±1.6 mol/g in the control hearts. The creatine phosphate (CP) levels of adenosine hearts were significantly lower than those of the control group before ischaemia, but did not show major differences following ischaemia.During ischaemia, the contractile activity measured via an intraventricular balloon catheter, as well as ischaemic contracture did not differ between the adenosine and control hearts. The inclusion of diltiazem into the perfusate significantly delayed the onset of contracture.After 45 min of reperfusion, ATP contents of adenosine and control hearts reached similar values (8.4±2.3 and 8.3±2.9 mol/g, respectively). Inclusion of adenosine (15 mol/l in the reperfusion perfusate of the adenosine experiments prevented a further decrease, but did not increase tissue ATP content. CP values of all groups showed a partial recovery upon reperfusion, they did not differ significantly.Contractile recovery was equal in all experimental groups except for the diltiazem treated hearts, which showed during the first 10 min of reperfusion an improved mechanical performance.It is concluded that total tissue ATP is not necessarily a good indicator of functional capabilities under conditions of normothermic ischaemia and reperfusion in the isolated rat heart.This work was supported in part by grants from the British heart foundation, the British Council and the St. Thomas, Hospital Research Endowments Fund. The advice and assistance of Dr. M. Curtis and Mrs. C. Erlebach are gratefully acknowledged.     

Colored microspheres reveal interarterial microvascular anastomoses in canine myocardium

Summary While the presence of microvascular intercommunication within an individual myocardial arterial bed is well documented, there is a paucity of data to support the existence of anastomoses emanating from independent arterial beds. Simultaneous in-vivo infusion of two different colored microsphere suspensions into the left anterior descending (LAD) and left circumflex (LCx) coronary arteries identified a specific interface region of canine myocardium that was perfused by both arterial branches. Subsequent microscopic/morphometric analysis of 40 m serial sections in eight hearts revealed clustering of microspheres in their respective perfusion territories (red microspheres in the LAD region away from the interface, blue microspheres in the LCx field away from the interface), along with a mutually perfused borderzone. In each tissue section, two regions within this zone were identified and their maximum widths measured. One region was defined as the Interface Transition Zone (ITZ) (mean width=5251±770 m; mean±SD). This region was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. The second region was defined as the Boundary Watershed Zone (BWZ) (mean zone width=3151±611 m; mean ±SD). This region was formed by capillaries containing sphere aggregates of both colors; it was located exclusively within the ITZ. In addition, the ITZ and BWZ were significantly wider in subepicardial than in subendocardial regions (p<0.001).     

Oxygen free radical damage of isolated cardiomyocytes: comparative protective effect of radical scavengers and calcium antagonists

Summary Oxygen free radicals have been shown to play a major role in the development of perfusion abnormalities, contractile dysfunction, and irreversible injury in ischemic-reperfused myocardium. The aim of this study was to assess the direct protective effects of radical scavengers, calcium antagonists, and combination of these substances against free radical induced myocyte damage. Viability (% of rod-shaped cells) and adenine nucleotide content (AdN, high-pressure liquid chromatography) of isolated adult rat cardiomyocytes were measured after exposure to hypoxanthine (2 mM) and xanthine oxidase (25 mU/ml). After 90 min, viability of myocytes decreased to 4.2±3.4 % (mean±SEM) of pre-exposure control, and AdN decreased from 28.2±1.8 to 8.09±1.1 nmol/mg protein. Addition of catalase (1500 U/ml) resulted in the preservation of viability (77±6% of pre-exposure control, n=6, mean±SEM), and AdN 84±6%, p<0.001. These values are not significantly different from those measured in myocytes not exposed to free radicals (88±9% and 79±6%, respectively). Superoxide dismutase (2400 U/ml), dimethylthiourea (10 mM), and desferrioxamine (1 mM) did not preserve either viability or AdN. The calcium antagonist verapamil (10 M) also preserved myocyte viability significantly (23±9.7%, p<0.05 vs unprotected cells), but failed to prevent the loss of AdN (13.2±4%, not significant as compared to unprotected cells). Viability and AdN in myocytes treated with nifedipine (10 M) or diltiazem (10 M) were not higher than in unprotected cells. All combined treatment forms which included catalase resulted in the preservation of myocyte viability as well as AdN. These data show that only the hydrogen peroxide scavenger catalase protects isolated cardiomyocytes against free radicals generated in the purine catabolic pathway.     

Fluoro-fatty acids and the impairment of cardiac function in the rat in vivo and in vitro

Summary Dichapetalum toxicarium seeds contain long chain fluoro-fatty acids, particularly fluorooleic acid, which in doses as low as 10 mg/kg can cause death. We have used the rat heart both in vivo and in vitro to assess the cardiovascular effects of various doses of the fluoro-oleic acid extract of the seeds ofDichapetalum toxicarium. Intraperitoneal administration of 0.25 ml of seed extract solution/kg body weight (estimated to be equivalent to 10 mg fluoro-oleic acid/kg body weight) or 0.5 ml/kg body weight (equivalent to 20 mg fluoro-oleic acid/kg body weight) resulted in death in all animals (n–6 in each group). The mean time from administration to death was 36.4±4 h and 21.0±2 h, respectively. Death was attributable to severe bradycardia which developed progressively throughout the experiment. Thus, during the first 6 h, heart rate fell by 32.2% from 450±7 beats/min to 305±36 beats/min (p<0.01) in the 0.25 ml/kg group and by 66±10% to 150±20 beats/min (p<0.001) in the 0.5 ml/kg group. Administration of the extract solution alone or oleic acid alone (equivalent to 0.5 ml/kg seed extract) to control rats had no effect. Investigating the effects of the seed extract in vitro, hearts (n=6 in each group) were perfused with buffer containing 0.5 ml/l seed extract (equivalent to 20 mg fluoro-oleic acid/l) or with buffer containing extract solution alone. In control hearts, there were no changes in heart rate or LVEDP over 150 min of aerobic perfusion; there were small declines in coronary flow, LVDP and LVdP/dt_max. Perfusion with seed extract resulted in a progressive decline in heart rate which, over the first 60 min of perfusion, fell by 53±7% from its control value of 323±11 beats/min to 153±20 beats/min (p<0.001). Similarly, significant declines in coronaryflow (fell by 53±12% over 60 min), LVDP (fell by 61±12% over 60 min) and LVdP/dt_max (fell by 63±7% over 60 min) were observed. LVEDP began to increase after 30 min and by 60 min had increased to 2.8±0.4 kPa (control value=0 kPa). Perfusion with oleic acid (20 mg/l) alone had no adverse effect on cardiac contractile function. Metabolic studies showed that the administration of the seed extract resulted in a loss of myocardial high energy phosphates. Thus, ATP and creatine phosphate fell from their control values of 20.6±0.4 and 27.8±0.6 mol/g dry weight to 3.9±0.4 and 2.4±0.4 mol/g dry weight (p<0.001 in each instance), respectively. Lactic acid content increased from 1.4±0.2 to 21.7±1.4 mol/g dry weight (p<0.001). In conclusion, our results indicate that the fluoro-oleic acid-containing extract ofDichapetalum toxicarium exerts its toxic effects by severely reducing cardiac function. In vivo this can lead to death of the animal.     

Does the antiarrhythmic effect of DMPO originate from its oxygen radical trapping property or the structure of the molecule itself?

Summary Using the isolated perfused rat heart with transient (30 min) normothermic global ischemia, it was shown that DMPO (5,5-dimethyl-pyrroline-N-oxide), an organic spin trap agent designed specifically to trap free radicals, dramatically reduced the vulnerability of the myocardium to reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT). DMPO (concentration range 30–500 mol/l) infused in the heart at the moment and during the first 10 min of reperfusion exerted a dose-dependent antiarrhythmic effect. Thus, the doses of 30, 100, and 500 mol/l of DMPO reduced the incidence of reperfusion-induced VF and VT from their control values of 100% and 100% to 83% and 91%, 50% (p<0.05) and 67%, 25% (p<0.01) and 50 (p<0.05), respectively. Furthermore, the recovery of myocardial function was improved during postischemic reperfusion. A modification in the molecular structure of DMPO leading to HMIO (1,2,2,4,5,5-hexamethyl-3-imidazoline-oxide), so-called inactive DMPO which does not trap free radicals in the presence of a radical generating system or in the effluent of reperfused hearts, failed to reduce the incidence of reperfusion-induced arrhythmias or improve the recovery of postischemic reperfused myocardium. These findings suggest that the free radical trapping properties of DMPO or the effects of the formed DMPO-OH, a stable nitroxyl radical adduct, are responsible for the reduction of reperfusion-induced arrhythmias, and not the molecular structure of DMPO itself. Finally, it is of interest to note that the detection of free radicals was observed in fibrillating hearts, but not in nonfibrillating hearts. This consideration should be taken into account when making therapeutic interventions and risk assessments of a radical scavenger in this setting.     

Recruitment of a time-dependent inotropic reserve by postextrasystolic potentiation in normal and reperfused myocardium

Summary Impaired excitation-contraction coupling has been suggested as the underlying mechanism of postischemic contractile dysfunction of reperfused myocardium in in-vitro studies. To test this hypothesis in situ, postextrasystolic potentiation (PESP) following an extrasystole with constant prematurity and three different postextrasystolic time intervals (compensated, regular, abbreviated) was analyzed in 12 anesthetized dogs. Changes in regional inotropic state were assessed by comparison of end-systolic wall thickness (sonomicrometry) during PESP to the respective pressure-matched values of an end-systolic pressure/wall-thickness relationship established during brief manual clamping of the aorta. Before ischemia, posterior end-systolic wall-thickness was increased by 0.19±0.35 (SD) mm during PESP with an abbreviated, by 0.36±0.42 mm with a regular, and by 0.60±0.42 mm with a compensated postextrasystolic interval. Bascline systolic wall thickening was decreased from 16.2±5.4% (before ischemia) to –3.0±3.4% at the end of 15 min left circumflex coronary occlusion, and to 2.8±7.5% at 10 min, 7.2±3.9% at 4 h, and 7.9±4.1% at 8 h reperfusion. Stepwise increases in regional inotropic state during PESP with increasing postextrasystolic intervals were not different in normal and reperfused myocardium. Thus, excitation-contraction coupling appears not to be impaired during inotropic stimulation of reperfused myocardium in situ.Supported by grant He 1320/3-2 of the German Research Foundation. This study is part of S. Schäfer's MD thesis.     

Open chest and open pericardium affect the distribution of myocardial blood flow in the right ventricle

Summary We have investigated the effects of open chest and open pericardium on the distribution of myocardial blood flow assessed with the radioactive microsphere technique (15 m). Five dogs with intact thorax served as controls (group I) and six dogs were studied after a right-sided thoracotomy and pericardiotomy (group II). Global myocardial blood flow (mean±S.D.) was 0.73±0.17 ml·min^–1·g^–1 in group I and 1.22±0.09 ml·min^–1·g^–1 in group II (p<0.05). Analysis of transmural blood flow distribution revealed that flow was 44% higher in the right and 60% higher in the left ventricular endocardial layers in the open-chest animals, whereas epicardial flow increased by 105% and 90%, respectively. As a result of the preferential blood flow to the epicardial layers of the right ventricle, the endo/epi ratio was reduced from 1.30±0.26 in group I to 0.86±0.11 in the open-chest group (p<0.05). Left ventricular endo/epi ratio was 1.27±0.16 and 1.06±0.11 (n.s.), respectively. External work and diastolic filling pressure of the right ventricle did not differ between the two groups and therefore cannot account for the redistribution of myocardial blood flow. It is concluded that the distribution of myocardial blood flow, particularly in the RV, is severely disturbed by thoracotomy and pericardiotomy. This is an important aspect for the planning and evaluation of studies under open-chest/open-pericardium conditions.Supported by Deutsche Forschungsgemeinschaft grant SFB 320     

Atrial natriuretic peptide decreases hepatic and cardiac blood content,but increases intestinal blood content in supine humans

Summary The authors evaluated in humans whether atrial natriuretic peptide (ANP) alters the regional distribution of blood in capacitance vessels. Eight healthy male volunteers (mean age: 30 years, range: 24–39) were studied twice. On different days and in a randomized, double blind fashion they received either h-ANP (99–126), 25 g intravenously followed by infusion of 0.1 kg^–1 min^–1, or vehicle. Changes of regional blood content in heart, liver, and intestine were evaluated at 3-min intervals using autologous radioactively (^99mTc) labeled red cells. Calf circumference (strain gauge) central venous pressure, and heart rate were recorded continuously while arterial pressure (oscillometry), hematocrit, ANP and cGMP plasma concentrations were determined intermittently.Exogenous ANP increased plasma concentrations of ANP (49 pg ml^–1±8 SE to 614±190) and cGMP (1.7 pmol ml^–1±0.2 to 30.8±4.4). This elicited significant and profound decreases in liver (–11%) and cardiac (–10%) radioactivity, contrasted by a smaller but significant increase (+4%) of intestinal radioactivity. These changes became gradually apparent about 15 min during ANP administration and reached their nadir at the end of the infusion period. Central venous pressure significantly decreased by 3.4 cm H₂O and calf volume by 0.3 ml/100 ml while hematocrit increased by 2.6%. All changes were at least partly reversed when ANP administration ceased. Of note, two subjects developed a near syncope with abrupt bradycardia and arterial hypotension following an initial gradual decrease in cardiac counts and central venous pressure.We conclude that in humans ANP markedly alters the regional blood distribution in the capacitance vasculature as blood content decreased profoundly in both heart and liver, but increased in the intestine, albeit to a lesser extent. Accordingly, a redistribution of blood away from the heart represents another unique mechanism by which ANP can exert its cardiovascular actions.The support by a grant (Ar 64/7) from the Deutsche Forschungsgemeinschaft to Drs. Arndt and Peters is gratefully acknowledged     

The interaction of the Bainbridge and Bezold-Jarisch reflexes in the conscious dog

Summary Experiments were undertaken to determine the efferent path of the Bainbridge reflex and to investigate the interaction of the Bainbridge reflex with the Bezold-Jarisch reflex in conscious, chronically instrumented dogs. The Bainbridge reflex was elicited by distending the left atrium by inflating a chronically implanted balloon catheter. The Bezold-Jarisch reflex was elicited using chemical stimulation of left ventricular receptors with infusions of veratridine (0.1–0.8 g/kg/min) into the left circumflex coronary artery. Heart-rate responses to left atrial balloon inflation were compared before and after either -1 antagonism with metoprolol or cholinergic antagonism with atropine, and before and during left ventricular receptor stimulation with intracoronary veratridine. Left atrial balloon inflation alone caused a significant increase in heart rate (70.1 ± 5 bpm), left atrial pressure (14 ± 3 mm Hg) and mean arterial blood pressure (10 ± 2 mm Hg). Heart-rate responses to left atrial distension were inhibited, but not abolished by either cholinergic or -1 antagonism. Left atrial distension after both cholinergic and -1 antagonism abolished the heart-rate response to balloon inflation. These results indicate that the efferent component of the Bainbridge reflex has both a vagal and a sympathetic component in conscious dogs. Left atrial distension during simultaneous left ventricular receptor stimulation resulted in a significantly decreased tachycardia than did left atrial distension alone (26 ± 3 bpm compared to 68 ± 8 bpm in the control experiments). In addition, the slope of the heart rate vs left atrial pressure relationship was significantly inhibited by left ventricular receptor stimulation (1.8 ± 0.2 bpm/mm Hg compared to 5.7 ± 0.3 bpm/mm Hg in the control experiments). There were no significant differences in either the left atrial pressure or arterial blood pressure changes between the two groups. These data suggest an interaction between these two reflexes that may be occurring in the central nervous system.Supported by funds from NIH grant HL-33359 and by a pre-doctoral fellowship from the Nebraska affiliate of the American Heart Association     

The digoxin-amiodarone interaction

Summary To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4–8 months.Mean (±SD) peak plasma digoxin concentration rose from 1.55±0.6 g/l prior to amiodarone therapy to 2.85±1.3 g/l after 1 week of combined therapy (p<0.01). Mean AUC also rose from 7.2±2.1 g/l.h to 12.1±6.4 g/l.h (p<0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4–8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses.This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.     

Effect of coronary hyperperfusion on regional myocardial function and oxygen consumption of stunned myocardium in pigs

Summary The Gregg phenomenon implies that myocardial function and oxygen consumption ( ) increase when coronary perfusion is enhanced within or above the autoregulatory range. We have recently demonstrated that the Gregg phenomenon has no significance for regional myocardial function and in anesthetized swine in situ. There is, however, some evidence that the Gregg phenomenon may exist within stunned myocardium. To test whether coronary hyperperfusion increases regional myocardial function and in stunned myocardium, in six anesthetized swine the left anterior descending coronary artery (LAD) was cannulated and perfused at constant pressure (CAP) using an extracorporal circuit. The coronary vein which parallels the LAD was cannulated to allow measurement of regional and regional systolic wall thickening (WT%) of the anterior myocardium was assessed using sonomicrometry. Blood flow (CBF) to the LAD was increased by increasing CAP within the extracorporal circuit or by intracoronary adenosine infusion (150 g/min). In normal myocardium, increasing CBF from 71.4 ± 19.7 (SD) to 156.7 ± 48.8 ml/min/100 g by increasing CAP from 100 ± 10 to 190 ± 10 mm Hg or increasing CBF from 75.1 ± 29.1 to 189.2 ± 45.8 ml/min/100 g by intracoronary adenosine infusion did not increase WT% (34.3 ± 12.2 % vs 32.1 ± 10.6 % and 32.3 ± 10.7 % vs 30.1 ± 13.2 %, respectively). was not changed during enhanced CAP (6.94 ± 1.05 vs 8.10 ± 1.08 ml/min/100 g) and during intracoronary adenosine infusion (6.67 ± 1.45 vs 7.30 ± 2.23 ml/min/100 g). Twenty min of hypoperfusion followed by 30 min of reperfusion depressed WT% by 47 % (p < 0.05). However, was only decreased by 23 % (NS). In the stunned myocardium, increasing CBF from 62.1 ± 36.4 to 157.1 ± 60.0 ml/min by increasing CAP was not associated with an increase in WT%. , however, increased from 5.14 ± 1.07 to 8.88 ± 1.83 ml/min/100 g (p < 0.05). Comparable results were achieved when CBF was increased from 60.3 ± 28.7 to 176.9 ± 48.5 ml/min by intracoronary adenosine infusion. WT% was unaffected, while increased from 4.69 ± 0.92 to 9.46 ± 3.39 ml/min/100 g (p < 0.05). Thus, increasing coronary perfusion within or above the autoregulatory range increases in stunned myocardium, but without a simultaneous increase in regional myocardial function.     

Protective effect of 7-oxo-prostacyclin on myocardial function and metabolism during postischemic reperfusion and calcium paradox

Summary The effect of 7-oxo PGI₂ on function and metabolism of postischemic reperfused (30-min ischemia and 30-min reperfusion) rat hearts was studied with special regard to calcium overload as one of the main factors of the postischemic reperfusion damage to the heart. The drug (50 g/kg i.p.) was applied 48 h prior to starting the experiments on isolated rat hearts (Langendorff preparation at 37 °C and constant perfusion pressure of 65 mm Hg). A late protective effect of 7-oxo PGI₂ was manifested by an improved recovery of heart function during reperfusion and calcium overload, better preservation of myocardial ATP contents during ischemia and also after calcium overload, as well as by a normalization of the lactate content, otherwise extremely increased during ischemia. Electron microscopic data also supported the above results. The beneficial effect of pretreatment with PGI₂ may be explained not only by its vasodilating action, but more by its membrane stabilizing effect with a consequently decreased sodium accumulation, potassium loss, as well as intracellular calcium overload.     

Vasoconstrictions mediated by an endothelium-derived vasoconstricting factor (EDCF)

Summary To enlighten the role of endothelium in the generation of vasospasms we examined vascular tone after reduction of oxygen supply in dependence on endothelial function in isolated vessels (rabbit aorta abdominalis, pig coronary, and pulmonary artery). Therefore, after ligation of all side branches, vessel segments, prepared either with or without endothelium, were cannulated and arranged in two systems (with two segments each) in a serial manner (system I: endothelium-denuded vessel followed by an endothelium-denuded segment) and perfused with Tyrode's solution (constant flow 20 ml/min). Pressure gradient over each segment was continuously measured. Endothelial function was checked by perfusion with 1 mol/l actetylholine after precontraction with 0.1 mol/l norepinephrine, thereby inducing an EDRF mediated vasodilation (>70%) indicating normal endothelial function. After 2 h equilibration with Tyrode's solution the preparations of rabbit aorta abdominalis were perfused for 30 min with oxygen-deprived medium (reduction from 95% O₂ and 5% CO₂ to 95% N₂ and 5% CO₂) and a marked long lasting (60 min) increase in pressure gradient (indicating vasoconstriction) was observed in those endothelium-denuded vessel segments which were mounted distal to a normal vessel with an intact endothelium. This contraction could be inhibited by pretreatment with either 1 mol/l dexamethasone, 1 mol/l indomethacine or 10 mol/l methylene blue or attenuated by the TXA₂-antagonist BM 17133 (5 mol/l) but not by radical scavengers as superoxid dismutase or by inhibition of the lipoxygenase by nordihydroguaretic acid. From these results it is concluded that endothelium releases a vasoconstricting factor (EDCF) at pO₂ values beneath 550 mm Hg. This EDCF seems to depend on phospholipase A₂ and cyclooxygenase, but because of the long-lasting effect it is probably no prostanoid itself, especially not TXA₂.     

Antiischemic effects of alinidine in paced isolated rat hearts

Summary Low-flow perfusion of paced (5 Hz) rat heart Langendorff preparation with Tyrode solution for 60 min caused a reduction or disappearance of left ventricular pressure amplitude. After 60 min of low-flow perfusion myocardial concentrations of high energy phosphates, as well as the energy charged potential, were diminished while lactate accumulated. Infusion of alinidine into the perfusate at low-flow conditions, resulted in a mean concentration of 15.0±0.60 M, and prevented the mechanical and biochemical changes of low-flow perfusion, thus indicating maintenance of acrobic metabolism under hypoxic conditions. These heart rate-independent cardioprotective effects of the specific bradycardic drug alinidine are discussed in light of the adenosine antagonistic actions of this compound which should prevent coronary steal.     

Effect of metoprolol on activity of β-adrenoceptor coupled to guanine nucleotide binding regulatory proteins in adriamycin-induced cardiotoxicity

Summary Prevention of cardiotoxicity without interfering with the therapeutic efficacy of adriamycin is a very crucial question. We have investigated the activity of -adrenoceptor coupled to guanine nucleotide binding regulatory proteins (G-proteins) and Ca²⁺-ATPase activity in experimental adriamycin-induced cardiotoxicity and the influence of metoprolol treatment on these variables. Adriamycin was administered to rats intravenously as a single dose of 6 mg/kg, and metoprolol was continuously given by means of implanted osmotic pumps. -adrenoceptor characteristics were measured by radioligand-binding experiments and by basal and stimulated adenylyl cyclase activity. Northern blot and dot blot analysis was used to quantify G-protein mRNA. It was shown that adriamycin did not induce any change in the total -adrenoceptor density, nor did the high affinity agonist binding to -adrenoceptor change. Adriamycin did not induce any alteration in the amount of mRNA encoding for stimulatory (Gs) or inhibitory (Gi) G-proteins. Also, basal and stimulated adenylyl cyclase activities were identical in the different experimental groups. In contrast, the Ca²⁺-ATPase was shown to increase in adriamycin-treated rats compared to control rats (45 ± 3.8 versus 23 ± 1.2 mol Pi/mg/h, P < .01). Metoprolol was shown to normalize this increase (29 ± 2.1 mol Pi/mg/h). Thus, it may be concluded that in experimental adriamycin-induced cardiotoxicity, despite Ca²⁺-overloading, the -adrenoceptor-G protein-adenylyl cyclase system remains intact. Metoprolol seems to prevent Ca²⁺-overloading independently of the -adrenoceptors studied here.